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1.
Alzheimers Dement ; 16(1): 11-21, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914230

RESUMO

INTRODUCTION: Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. METHODS: Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. RESULTS: NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. DISCUSSION: The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

2.
Alzheimers Dement ; 16(1): 106-117, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914218

RESUMO

INTRODUCTION: We created global rating scoring rules for the CDR® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD. METHODS: The CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants. RESULTS: The CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non-fluent/agrammatic variant primary progressive aphasia participants. DISCUSSION: The global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

3.
Neurobiol Aging ; 88: 42-50, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31918955

RESUMO

Loss-of-function mutations in the progranulin gene (GRN) are one of the major causes of familial frontotemporal lobar degeneration. Our objective was to determine the rates and trajectories of lobar cortical atrophy from longitudinal structural magnetic resonance imaging in both asymptomatic and symptomatic GRN mutation carriers. Individuals in this study were from the ADRC and LEFFTDS studies at the Mayo Clinic. We identified 13 GRN mutation carriers (8 asymptomatic, 5 symptomatic) and noncarriers (n = 10) who had at least 2 serial T1-weighted structural magnetic resonance images and were followed annually with a median of 3 years (range 1.0-9.8 years). Longitudinal changes in lobar cortical volume were analyzed using the tensor-based morphometry with symmetric normalization (TBM-SyN) algorithm. Linear mixed-effect models were used to model cortical volume change over time among 3 groups. The annual rates of frontal (p < 0.05) and parietal (p < 0.01) lobe cortical atrophy were higher in asymptomatic GRN mutation carriers than noncarriers. The symptomatic GRN mutation carriers also had increased rates of atrophy in the frontal (p < 0.01) and parietal lobe (p < 0.01) cortices than noncarriers. In addition, greater rates of cortical atrophy were observed in the temporal lobe cortices of symptomatic GRN mutation carriers than noncarriers (p < 0.001). We found that a decline in frontal and parietal lobar cortical volume occurs in asymptomatic GRN mutation carriers and continues in the symptomatic GRN mutation carriers, whereas an increased rate of temporal lobe cortical atrophy is observed only in symptomatic GRN mutation carriers. This sequential pattern of cortical involvement in GRN mutation carriers has important implications for using imaging biomarkers of neurodegeneration as an outcome measure in potential treatment trials involving GRN mutation carriers.

4.
Alzheimers Dement ; 16(1): 37-48, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31272932

RESUMO

INTRODUCTION: Some models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset. METHODS: We created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor. RESULTS: Cross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]). DISCUSSION: Individualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.

5.
Alzheimers Dement ; 16(1): 22-36, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31636026

RESUMO

INTRODUCTION: It is important to establish the natural history of familial frontotemporal lobar degeneration (f-FTLD) and provide clinical and biomarker data for planning these studies, particularly in the asymptomatic phase. METHODS: The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects protocol was designed to enroll and follow at least 300 subjects for more than at least three annual visits who are members of kindreds with a mutation in one of the three most common f-FTLD genes-microtubule-associated protein tau, progranulin, or chromosome 9 open reading frame 72. RESULTS: We present the theoretical considerations of f-FTLD and the aims/objectives of this protocol. We also describe the design and methodology for evaluating and rating subjects, in which detailed clinical and neuropsychological assessments are performed, biofluid samples are collected, and magnetic resonance imaging scans are performed using a standard protocol. DISCUSSION: These data and samples, which are available to interested investigators worldwide, will facilitate planning for upcoming disease-modifying therapeutic trials in f-FTLD.

6.
Alzheimers Dement ; 16(1): 49-59, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31784375

RESUMO

INTRODUCTION: The Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations. METHODS: We examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non-mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia. RESULTS: Asymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self-monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects. DISCUSSION: Imaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

7.
Neurobiol Aging ; 83: 54-62, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31585367

RESUMO

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials.

8.
Alzheimers Dement (N Y) ; 5: 338-346, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31388560

RESUMO

Introduction: The aim of this study was to investigate the rates of lobar atrophy in the asymptomatic microtubule-associated protein tau (MAPT) mutation carriers. Methods: MAPT mutation carriers (n = 14; 10 asymptomatic, 4 converters from asymptomatic to symptomatic) and noncarriers (n = 13) underwent structural magnetic resonance imaging and were followed annually with a median of 9.2 years. Longitudinal changes in lobar atrophy were analyzed using the tensor-based morphometry with symmetric normalization algorithm. Results: The rate of temporal lobe atrophy in asymptomatic MAPT mutation carriers was faster than that in noncarriers. Although the greatest rate of atrophy was observed in the temporal lobe in converters, they also had increased atrophy rates in the frontal and parietal lobes compared to noncarriers. Discussion: Accelerated decline in temporal lobe volume occurs in asymptomatic MAPT mutation carriers followed by the frontal and parietal lobe in those who have become symptomatic. The findings have implications for monitoring the progression of neurodegeneration during clinical trials in asymptomatic MAPT mutation carriers.

9.
Neurology ; 93(8): e758-e765, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31315971

RESUMO

OBJECTIVE: To determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations. METHODS: We recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons. RESULTS: Asymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset. CONCLUSION: Frontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.


Assuntos
Ácido Aspártico/análogos & derivados , Creatina/metabolismo , Demência/metabolismo , Lobo Frontal/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Inositol/metabolismo , Proteínas tau/metabolismo , Adulto , Ácido Aspártico/metabolismo , Doenças Assintomáticas , Biomarcadores/metabolismo , Estudos de Casos e Controles , Demência/complicações , Demência/genética , Feminino , Degeneração Lobar Frontotemporal/complicações , Degeneração Lobar Frontotemporal/diagnóstico , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Espectroscopia de Prótons por Ressonância Magnética , Adulto Jovem , Proteínas tau/genética
10.
J Neuroimaging ; 29(5): 624-629, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31173437

RESUMO

BACKGROUND AND PURPOSE: The objective of this study was to longitudinally investigate the trajectory of change in 1 H MRS measurements in asymptomatic MAPT mutation carriers who became symptomatic during follow-up, and to determine the time at which the neurochemical alterations accelerated during disease progression. METHODS: We identified eight MAPT mutations carriers who transitioned from asymptomatic to symptomatic disease during follow-up. All participants were longitudinally followed with an average of 7.75 years (range 4-11 years) and underwent two or more single voxel 1 H MRS examinations from the posterior cingulate voxel, with a total of 60 examinations. The rate of longitudinal change for each metabolite was estimated using linear mixed models. A flex point model was used to estimate the flex time point of the change in slope. RESULTS: The decrease in the NAA/mI ratio accelerated 2.09 years prior to symptom onset, and continued to decline. A similar trajectory was observed in the presumed glial marker mI/Cr ratio accelerating 1.86 years prior to symptom onset. CONCLUSIONS: Our findings support the potential use of longitudinal 1 H MRS for monitoring the neurodegenerative progression in MAPT mutation carriers starting from the asymptomatic stage.

11.
Alzheimers Dement ; 2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31088775

RESUMO

INTRODUCTION: Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. METHODS: Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. RESULTS: NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. DISCUSSION: The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

13.
Int J Neuropsychopharmacol ; 13(6): 799-805, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20059802

RESUMO

There is growing evidence of neurotrophin alterations in neuropsychiatric illnesses such as schizophrenia and further, neurotransmitters known to be adversely affected in schizophrenia (e.g. dopamine) can activate neurotrophin signalling pathways via G protein-coupled receptors. However, it is unclear how the primary therapeutic agents used in schizophrenia affect neurotrophin signalling. This is important given that all currently prescribed antipsychotic drugs serve as ligands at dopamine receptors. In this study, chronic effects of representative conventional and second-generation antipsychotics on nerve growth factor (NGF) receptor levels were assessed in the rat. The results indicated no significant drug effects on TrkA levels in any brain region analysed; however, three of the five antipsychotics analysed significantly decreased phospho-TrkA (i.e. the activated form of the receptor) in the hippocampus. These data indicate that chronic antipsychotic treatment may result in deleterious effects on neurotrophin signalling in an important brain region for information processing and cognition.


Assuntos
Antipsicóticos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Receptor trkA/metabolismo , Administração Oral , Análise de Variância , Animais , Antipsicóticos/sangue , Esquema de Medicação , Ensaio de Imunoadsorção Enzimática/métodos , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar
14.
Neurobiol Aging ; 29(2): 185-93, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17157413

RESUMO

From a normal human brain phage display library screen we identified the gamma (A)-globin chain of fetal hemoglobin (Hb F) as a protein that bound strongly to A beta1-42. We showed the oxidized form of adult Hb (metHb A) binds with greater affinity to A beta1-42 than metHb F. MetHb is more toxic than oxyhemoglobin because it loses its heme group more readily. Free Hb and heme readily damage vascular endothelial cells similar to Alzheimer's disease (AD) vascular pathology. The XmnI polymorphism (C-->T) at -158 of the gamma (G)-globin promoter region can contribute to increased Hb F expression. Using family-based association testing, we found a significant protective association of this polymorphism in the NIMH sibling dataset (n=489) in families, with at least two affected and one unaffected sibling (p=0.006), with an age of onset >50 years (p=0.010) and >65 years (p=0.013), and families not homozygous for the APOE4 allele (p=0.041). We hypothesize that Hb F may be less toxic than adult Hb in its interaction with A beta and may protect against the development of AD.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Hemoglobinas/metabolismo , Fragmentos de Peptídeos/metabolismo , Polimorfismo Genético , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Apolipoproteína E4/genética , Desoxirribonucleases de Sítio Específico do Tipo II , Saúde da Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ressonância de Plasmônio de Superfície/métodos
15.
Eur J Pharmacol ; 571(1): 29-32, 2007 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-17601556

RESUMO

Alpha(7) nicotinic acetylcholine receptor deficits may contribute to cognitive dysfunction in schizophrenia; however, the contribution of antipsychotic drug exposure to these deficits is unknown. In this study, rats were treated orally with haloperidol (2.0 mg/kg/day) or risperidone (2.5 mg/kg/day) for 15 or 90 days. Subsequent immunoassays indicated that both antipsychotics were associated with alpha(7) nicotinic receptor decreases in the basal forebrain and prefrontal cortex when administered for 90 (but not 15) days, a result that was confirmed in autoradiographic experiments. These data suggest that haloperidol and risperidone may be associated with time dependent decreases in an important neurobiological substrate of memory.


Assuntos
Haloperidol/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Prosencéfalo/efeitos dos fármacos , Receptores Nicotínicos/metabolismo , Risperidona/farmacologia , Administração Oral , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacologia , Autorradiografia , Ensaio de Imunoadsorção Enzimática , Haloperidol/administração & dosagem , Córtex Pré-Frontal/metabolismo , Prosencéfalo/metabolismo , Ratos , Ratos Wistar , Risperidona/administração & dosagem , Fatores de Tempo , Receptor Nicotínico de Acetilcolina alfa7
16.
J Pharmacol Exp Ther ; 322(3): 1117-28, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17548533

RESUMO

Persistent behavioral abnormalities have been commonly associated with acute organophosphate (OP) pesticide poisoning; however, relatively little is known about the consequences of chronic OP exposures that are not associated with acute cholinergic symptoms. In this study, the behavioral and neurochemical effects of chronic, intermittent, and subthreshold exposures to the OP pesticide, chlorpyrifos (CPF), were investigated. Rats were injected with CPF s.c. (dose range, 2.5-18.0 mg/kg) every other day over the course of 30 days and then were given a 2-week CPF-free washout period. In behavioral experiments conducted during the washout period, dose-dependent decrements in a water-maze hidden platform task and a prepulse inhibition procedure were observed, without significant effects on open-field activity, Rotorod performance, grip strength, or a spontaneous novel object recognition task. After washout, levels of CPF and its metabolite 3,5,6-trichloro-2-pyridinol were minimal in plasma and brain; however, cholinesterase inhibition was still detectable. Furthermore, the 18.0 mg/kg dose of CPF was associated with (brain region-dependent) decreases in nerve growth factor receptors and cholinergic proteins including the vesicular acetylcholine transporter, the high-affinity choline transporter, and the alpha(7)-nicotinic acetylcholine receptor. These deficits were accompanied by decreases in anterograde and retrograde axonal transport measured in sciatic nerves ex vivo. Thus, low-level (intermittent) exposure to CPF has persistent effects on neurotrophin receptors and cholinergic proteins, possibly through inhibition of fast axonal transport. Such neurochemical changes may lead to deficits in information processing and cognitive function.


Assuntos
Transporte Axonal/efeitos dos fármacos , Clorpirifos/farmacologia , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Receptores de Fator de Crescimento Neural/efeitos dos fármacos , Receptores Nicotínicos/efeitos dos fármacos , Proteínas Vesiculares de Transporte de Acetilcolina/efeitos dos fármacos , Animais , Biomarcadores , Clorpirifos/toxicidade , Inibidores da Colinesterase , Relação Dose-Resposta a Droga , Esquema de Medicação , Inseticidas , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Fatores de Tempo , Receptor Nicotínico de Acetilcolina alfa7
17.
Cell Mol Biol Lett ; 12(1): 82-102, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17103092

RESUMO

The activity of indoleamine 2, 3-dioxygenase (IDO; E.C. 1.13.11.42) catalyzes the oxidative cleavage of tryptophan to form kynurenine. IDO activity consumes superoxide anions; therefore, we postulated that over-expression of IDO might mitigate superoxide-anion dependent, oxidative modification of cellular proteins in vitro. We prepared and characterized RAW 264.7 macrophages that were stably transfected with either an IDO expression vector or the control (empty) vector. We detected IDO mRNA, protein, and enzyme activity in the IDO-transfected macrophages, but not in the macrophages transfected with the empty vector. To generate superoxide anions in situ, we treated the IDO-and control-transfected cultures with xanthine or hypoxanthine, and then used ELISA methods to quantitate the relative levels of oxidatively modified proteins in total cell lysates. The levels of protein carbonyls were similar in IDO-transfected and vector-transfected macrophages; however, protein nitration was significantly less in IDO-transfected cells compared to control transfectants. In addition, steady-state levels of superoxide anions were significantly lower in the IDO-transfected cultures compared with control transfectants. Our results are consistent with the concept that, besides degrading tryptophan, IDO activity may protect cells from oxidative damage.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Macrófagos/enzimologia , Nitratos/metabolismo , Animais , Células Cultivadas , Regulação Enzimológica da Expressão Gênica , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Camundongos , Camundongos Endogâmicos BALB C , Carbonilação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Superóxidos/metabolismo , Transfecção
18.
Toxicol Appl Pharmacol ; 218(1): 20-9, 2007 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17123561

RESUMO

Diisopropylfluorophosphate, originally developed as a chemical warfare agent, is structurally similar to nerve agents, and chlorpyrifos has extensive worldwide use as an agricultural pesticide. While inhibition of cholinesterases underlies the acute toxicity of these organophosphates, we previously reported impaired axonal transport in the sciatic nerves from rats treated chronically with subthreshold doses of chlorpyrifos. Those data indicate that chlorpyrifos (and/or its active metabolite, chlorpyrifos-oxon) might directly affect the function of kinesin and/or microtubules--the principal proteins that mediate anterograde axonal transport. The current report describes in vitro assays to assess the concentration-dependent effects of chlorpyrifos (0-10 microM), chlorpyrifos-oxon (0-10 microM), and diisopropylfluorophosphate (0-0.59 nM) on kinesin-dependent microtubule motility. Preincubating bovine brain microtubules with the organophosphates did not alter kinesin-mediated microtubule motility. In contrast, preincubation of bovine brain kinesin with diisopropylfluorophosphate, chlorpyrifos, or chlorpyrifos-oxon produced a concentration-dependent increase in the number of locomoting microtubules that detached from the kinesin-coated glass cover slip. Our data suggest that the organophosphates-chlorpyrifos-oxon, chlorpyrifos, and diisopropylfluorophosphate-directly affect kinesin, thereby disrupting kinesin-dependent transport on microtubules. Kinesin-dependent movement of vesicles, organelles, and other cellular components along microtubules is fundamental to the organization of all eukaryotic cells, especially in neurons where organelles and proteins synthesized in the cell body must move down long axons to pre-synaptic sites in nerve terminals. We postulate that disruption of kinesin-dependent intracellular transport could account for some of the long-term effects of organophosphates on the peripheral and central nervous system.


Assuntos
Substâncias para a Guerra Química/toxicidade , Clorpirifos/análogos & derivados , Inibidores da Colinesterase/toxicidade , Cinesina/antagonistas & inibidores , Microtúbulos/efeitos dos fármacos , Praguicidas/toxicidade , Hidrolases de Triester Fosfórico/toxicidade , Animais , Transporte Axonal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica , Bovinos , Substâncias para a Guerra Química/química , Clorpirifos/química , Clorpirifos/toxicidade , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Técnicas In Vitro , Cinesina/isolamento & purificação , Cinesina/metabolismo , Estrutura Molecular , Praguicidas/química , Hidrolases de Triester Fosfórico/química , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/isolamento & purificação
19.
J Pharmacol Exp Ther ; 318(2): 709-24, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16702442

RESUMO

In this rodent study, we evaluated the effects of different time periods (7, 14, 45, and 90 days) of oral treatment with haloperidol (HAL; 2.0 mg/kg/day) or ziprasidone (ZIP; 12.0 mg/kg/day) on nerve growth factor (NGF) and choline acetyltransferase (ChAT) levels in the hippocampus, and we subsequently assessed water maze task performance, prepulse inhibition (PPI) of the auditory gating response, and several NGF-related proteins and cholinergic markers after 90 days of treatment. Seven and 14 days of treatment with either HAL or ZIP resulted in a notable increase in NGF and ChAT immunoreactivity in the dentate gyrus (DG), CA1, and CA3 areas of the hippocampus. After 45 days, NGF and ChAT immunoreactivity had abated to control levels in ZIP-treated animals, but it was markedly reduced in HAL-treated subjects. After 90 days of treatment, NGF and ChAT levels were substantially lower than controls in both antipsychotic groups. Furthermore, after 90 days of treatment and a drug-free washout period, water maze performance (but not PPI) was impaired in both antipsychotic groups, although the decrement was greater in the HAL group. Several NGF-related and cholinergic proteins were diminished in the brains of subjects treated with either neuroleptic as well. These data support the premise that, although ZIP (given chronically) seems somewhat superior to HAL due to less pronounced behavioral effects and a more delayed appearance of neurochemical deficits, both antipsychotics produce time-dependent deleterious effects on NGF, cholinergic markers (i.e., important neurobiological substrates of memory), and cognitive function.


Assuntos
Antipsicóticos/farmacologia , Haloperidol/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Sistema Nervoso Parassimpático/efeitos dos fármacos , Piperazinas/farmacologia , Tiazóis/farmacologia , Animais , Autorradiografia , Química Encefálica/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Escuridão , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Luz , Masculino , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Ratos , Ratos Wistar , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/metabolismo , Fatores de Tempo
20.
J Neurosci Methods ; 150(2): 159-73, 2006 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-16085318

RESUMO

The central cholinergic system has a fundamental role in normal cognitive function, and in diseases that exhibit cognitive dysfunction. The purpose of this study was to design ELISA methods to measure proteins that have essential functions in the central cholinergic system. We were particularly interested in quantifying proteins that respond directly or indirectly to nerve growth factor (NGF). ELISAs offer advantages over Western blot analyses and other methods, such as increased sensitivity, decreased assay variability, increased efficiency, and decreased cost. We developed indirect ELISA methods for: choline acetyltransferase (ChAT); the vesicular acetylcholine transporter (VAChT); the high affinity choline transporter (HACT/CHT); TrkA, the high affinity NGF receptor; the p75 neurotrophin receptor (p75(NTR)). A sandwich ELISA was developed to measure tyrosine-phosphorylated TrkA in brain lysates. We used these ELISAs to compare levels of the above proteins in important memory-related brain regions--basal forebrain, hippocampus, cortex, and prefrontal cortex--from old and young rats. We identified age-related differences in the levels of the aforementioned proteins (e.g., VAChT and HACT/CHT in hippocampus). Thus, these ELISA methods should be particularly useful for comparing the effects of age, disease, drugs, and toxicants on brain levels of key cholinergic and growth factor-related proteins.


Assuntos
Acetilcolina/metabolismo , Biomarcadores/análise , Química Encefálica/fisiologia , Ensaio de Imunoadsorção Enzimática/métodos , Fator de Crescimento Neural/análise , Fatores Etários , Animais , Western Blotting , Masculino , Ratos
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